PROJECT SUMMARY/ABSTRACT Inflammatory bowel disease (IBD), comprised of ulcerative colitis (UC) and Crohn's disease (CD) are chronic disorders of the GI tract with rapidly increasing prevalence. Despite recent advances in treatment, a significant proportion of patients have suboptimal responses to medical therapy, leaving an urgent need to identify new therapies. One promising new approach to treat IBD is through the manipulation of regulatory T cells (Tregs). Thymically-derived Tregs are an immune modulating subset of CD4+ lymphocytes that antagonize the activation and effector function of multiple immune cell types and promote tolerance to self-antigens. Adoptively transferred Tregs are effective in murine models of IBD preventing both T cell-mediated and myeloid cell-mediated colitis, while Treg cell therapy has shown promise in the treatment of graft vs. host disease (GvHD) and type 1 diabetes. An alternative and attractive approach to disease management through Treg manipulation is to increase Treg numbers in vivo. Interleukin-2 (IL-2, Proleukin) is a T cell growth factor. IL-2 is currently licensed for the treatment of metastatic renal cell carcinoma and metastatic melanoma. At low doses, IL-2 promotes the selective activation and expansion of Tregs in humans. Tregs constitutively express CD25, a component of the high-affinity IL-2R, while CD25 is only transiently expressed by activated conventional T effector cells. Oncology collaborators on our team recently demonstrated that low-dose (LD) IL-2 selectively expands Tregs in humans in vivo and is safe in chronic GvHD, with efficacy in a phase 1 and 2 clinical trials. Our preliminary data shows that LD IL-2 selectively activates Tregs in lamina propria (LP) cells from patients with UC and that it is protective in a humanized mouse model of IBD. We therefore hypothesize that LD IL-2 will selectively expand Treg populations in vivo in patients with moderate-to-severe UC, and that expansion will be associated with a therapeutic response. To translate these pre-clinical findings to patient benefit, we have initiated a phase 1b/2a clinical trial of LD IL-2 in patients with UC. To date, we have enrolled 11 patients at the first two doses. LD IL-2 has been well tolerated and has resulted in a biological response, with an increase in peripheral blood Tregs at two different doses. This proposal addresses two specific aims: 1) To determine the safety of LD IL-2 in the treatment of moderate-to-severe UC, and 2) To determine whether LD IL-2 modulates peripheral blood and lamina propria Tregs in vivo in the setting of UC and to correlate this with clinical outcome. This trial is designed to determine the maximum tolerated dose and safety profile of LD IL-2 in this patient group, and to obtain a signal of efficacy.